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Broadly active zinc finger protein-guided transcriptional activation of HIV-1

Human immunodeficiency virus type 1 (HIV-1) causes a persistent viral infection resulting in the demise of immune regulatory cells. Clearance of HIV-1 infection results in integration of proviral DNA into the genome of host cells, which provides a means for evasion and long-term persistence. A thera...

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Autores principales: Scott, Tristan A., O’Meally, Denis, Grepo, Nicole Anne, Soemardy, Citradewi, Lazar, Daniel C., Zheng, Yue, Weinberg, Marc S., Planelles, Vicente, Morris, Kevin V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726486/
https://www.ncbi.nlm.nih.gov/pubmed/33335944
http://dx.doi.org/10.1016/j.omtm.2020.10.018
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author Scott, Tristan A.
O’Meally, Denis
Grepo, Nicole Anne
Soemardy, Citradewi
Lazar, Daniel C.
Zheng, Yue
Weinberg, Marc S.
Planelles, Vicente
Morris, Kevin V.
author_facet Scott, Tristan A.
O’Meally, Denis
Grepo, Nicole Anne
Soemardy, Citradewi
Lazar, Daniel C.
Zheng, Yue
Weinberg, Marc S.
Planelles, Vicente
Morris, Kevin V.
author_sort Scott, Tristan A.
collection PubMed
description Human immunodeficiency virus type 1 (HIV-1) causes a persistent viral infection resulting in the demise of immune regulatory cells. Clearance of HIV-1 infection results in integration of proviral DNA into the genome of host cells, which provides a means for evasion and long-term persistence. A therapeutic compound that specifically targets and sustainably activates a latent HIV-1 provirus could be transformative and is the goal for the “shock-and-kill” approach to a functional cure for HIV-1. Substantial progress has been made toward the development of recombinant proteins that target specific genomic loci for gene activation, repression, or inactivation by directed mutations. However, most of these modalities are too large or too complex for efficient therapeutic application. We describe here the development and testing of a novel recombinant zinc finger protein transactivator, ZFP-362-VPR, which specifically and potently enhances proviral HIV-1 transcription both in established latency models and activity across different viral clades. Additionally, ZFP-362-VPR-activated HIV-1 reporter gene expression in a well-established primary human CD4(+) T cell latency model and off-target pathways were determined by transcriptome analyses. This study provides clear proof of concept for the application of a novel, therapeutically relevant, protein transactivator to purge cellular reservoirs of HIV-1.
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spelling pubmed-77264862020-12-16 Broadly active zinc finger protein-guided transcriptional activation of HIV-1 Scott, Tristan A. O’Meally, Denis Grepo, Nicole Anne Soemardy, Citradewi Lazar, Daniel C. Zheng, Yue Weinberg, Marc S. Planelles, Vicente Morris, Kevin V. Mol Ther Methods Clin Dev Original Article Human immunodeficiency virus type 1 (HIV-1) causes a persistent viral infection resulting in the demise of immune regulatory cells. Clearance of HIV-1 infection results in integration of proviral DNA into the genome of host cells, which provides a means for evasion and long-term persistence. A therapeutic compound that specifically targets and sustainably activates a latent HIV-1 provirus could be transformative and is the goal for the “shock-and-kill” approach to a functional cure for HIV-1. Substantial progress has been made toward the development of recombinant proteins that target specific genomic loci for gene activation, repression, or inactivation by directed mutations. However, most of these modalities are too large or too complex for efficient therapeutic application. We describe here the development and testing of a novel recombinant zinc finger protein transactivator, ZFP-362-VPR, which specifically and potently enhances proviral HIV-1 transcription both in established latency models and activity across different viral clades. Additionally, ZFP-362-VPR-activated HIV-1 reporter gene expression in a well-established primary human CD4(+) T cell latency model and off-target pathways were determined by transcriptome analyses. This study provides clear proof of concept for the application of a novel, therapeutically relevant, protein transactivator to purge cellular reservoirs of HIV-1. American Society of Gene & Cell Therapy 2020-10-27 /pmc/articles/PMC7726486/ /pubmed/33335944 http://dx.doi.org/10.1016/j.omtm.2020.10.018 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Scott, Tristan A.
O’Meally, Denis
Grepo, Nicole Anne
Soemardy, Citradewi
Lazar, Daniel C.
Zheng, Yue
Weinberg, Marc S.
Planelles, Vicente
Morris, Kevin V.
Broadly active zinc finger protein-guided transcriptional activation of HIV-1
title Broadly active zinc finger protein-guided transcriptional activation of HIV-1
title_full Broadly active zinc finger protein-guided transcriptional activation of HIV-1
title_fullStr Broadly active zinc finger protein-guided transcriptional activation of HIV-1
title_full_unstemmed Broadly active zinc finger protein-guided transcriptional activation of HIV-1
title_short Broadly active zinc finger protein-guided transcriptional activation of HIV-1
title_sort broadly active zinc finger protein-guided transcriptional activation of hiv-1
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726486/
https://www.ncbi.nlm.nih.gov/pubmed/33335944
http://dx.doi.org/10.1016/j.omtm.2020.10.018
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